Paroxetine, (−)-(3S,4R)-4-(p-Fluorophenyl)-3-[[3,4-(methylenedioxy)phenoxy]methyl]piperidine, is an therapeutic agent of the type known as selective serotonin reuptake inhibitors. Paroxetine is a well characterized molecule in the pharmaceutical and patent literature. Chemical processes for its manufacture are detailed in U.S. Pat. Nos. 4,861,893; 6,172,233; 6,326,496; 6,433,179; 6,541,637 6,686,473; 6,716,985; 6,881,845; 6,900,327; and U.S. Pat. No. 6,956,121 to name a few. Paroxetine has also been indicated for a wide range of treatments but is primarily prescribed to treat depression, obsessive compulsive disorder, post-traumatic stress disorder, panic disorder, generalized anxiety disorder, social phobia and social anxiety disorders, and premenstrual dysphoric disorder. Common off-label uses of paroxetine include the treatment of premature ejaculation, compulsive gambling, hot flashes, diabetic neuropathy, and tension headache. Paroxetine is also sometimes used to treat chronic headaches, tingling in the hands and feet caused by diabetes, and certain male sexual problems. In addition to its use for psychiatric diseases and disorders, and psychological diseases and disorders, studies have also been conducted suggesting that paroxetine is beneficial for use in the treatment, alleviation and prevention of thermoregulatory dysfunctions and vasomotor symptoms including hot flashes and hot flushes, and potentially further for, night awakenings, night sweats, and other disorders and conditions associated with perimenopause, menopause and hormonal deficiencies.
The compound has been known both in its basic form and in the form of its pharmaceutically acceptable salts since at least 1977 with the publication of U.S. Pat. No. 4,007,196. The '196 patent makes explicit reference to the paroxetine base and to its maleate salt. Paroxetine is currently marketed in the US in the form of acidic salt, the hydrochloride salt, under the trade name PAXIL and as the mesylate salt under the PEXEVA trade name.
Paroxetine hydrochloride can be crystallized in either an anhydrate or a hemihydrate crystal form: the anhydrous form in several crystalline modifications (PCT Application WO 96/24595); the hydrated form—a hemihydrate (EP patent 223403) and in the solvated forms. The comparison of behavior between the anhydrous and hydrated form of paroxetine hydrochloride is described in the Intl. Journal of Pharmaceutics, 42, 135-143 (1988). EP Patent 223403 discloses paroxetine hydrochloride hemihydrate and pharmaceutical compositions based thereon.
Many of the known salts of paroxetine have unsuitable physico-chemical characteristics for ensuring safe and efficient handling during production thereof and formulation into final forms, since they are unstable (acetate, maleate) and possess undesirable hygroscopicity. Furthermore their formation by crystallization from both aqueous and non-aqueous solvents is generally low-yielding and troublesome as they usually contain an undefined and unpredictable amount of bound solvent which is difficult to remove. The crystalline paroxetine hydrochloride hemihydrate approaches these problems, but as stated in PCT Application WO 95/16448, its limited photostability causes undesired coloration during classical wet granulation procedures. Moreover, crystalline paroxetine hydrochloride hemihydrate exhibits only limited solubility in water.
Sulfonic acid salts of paroxetine, and their crystalline form, are described in U.S. Pat. Nos. 5,874,447 and 7,509,271. The '447 patent describes paroxetine sulfonate salts, including paroxetine methane sulfonate also known as paroxetine mesylate. These sulfonate salts have advantageous properties in comparison to the known salts, including the hydrochloride salts. For example, the sulfonate salts have high water solubility and good thermal stability, making them useful as a commercial paroxetine dosage form. The '447 patent discloses that tablets can be made by any known method including a dry technique (direct compression, dry granulation) or a wet technique (wet granulation). Example 1 of those patents describe the preparation of paroxetine mesylate, also known as the methane sulfonic acid salt of paroxetine, and shown in structural formula (I) below.

U.S. Pat. No. 6,063,927 “generally” refers to the ability to make the mesylate salt in a non-crystalline form (solid or an oil), and in solvated forms, but provides no specifics other than creating an acetonitrile solvated form, which is unsuitable for commercial application, and an amorphous form. U.S. Pat. No. 7,509,271describes the only crystalline form of paroxetine mesylate, an anhydrous crystalline form designated Form A). Paroxetine mesylate has no known polymorphs.
The amorphous form of a drug may temporarily provide a greater aqueous concentration of drug relative to the equilibrium concentration obtained by dissolution of the crystalline drug in a use environment. Such amorphous forms may consist as the amorphous drug alone, a solid dispersion of the amorphous drug in a matrix material, or the amorphous drug adsorbed onto a substrate. It is believed that such amorphous forms of the drug may dissolve more rapidly than the crystalline form, often dissolving faster than the drug can precipitate from solution. As a result, the amorphous form may temporarily provide a greater aqueous concentration of drug.
While such amorphous forms may show initially enhanced concentration of the drug in a use environment, nevertheless the improved concentration may often be short-lived. The initially enhanced drug concentration may be only temporary and quickly return to the lower equilibrium concentration of a crystalline form. Amorphous paroxetine mesylate may be generated through lyophilization from water having a glass transition temperature of approximately 44° C.; but it is physically unstable and over time converts to crystalline Form A. Various amorphous paroxetine compositions have been disclosed, for example, in U.S. Pat. Nos. 5,672,612, 6,503,927, 6,638,948, 6,169,805, 6,720,003, and 6,063,927.
As mentioned above, one approach to increasing the stability of amorphous drug forms involves forming dispersions of amorphous drugs with polymers. Use of amorphous compositions for advanced drug delivery systems includes oral capsules, an example of which is an amorphous paroxetine composition disclosed in PCT Application WO 99/16440. PCT Application WO 99/56751 describes amorphous paroxetine formulations which are produced by mixing paroxetine salts, preferably the hydrochloride, with water and a polymer and subsequently drying at 25 -100° C., preferably at 60° C. PCT Application WO 01/30349 likewise relates to the processing of amorphous paroxetine salts in polyvinylpyrrolidone and an additional acid. Production takes place at temperatures of 15-40° C. Other examples of attempts to form a dispersion of the drug with a polymer include U.S. Pat. Nos. 5,368,864, 5,707,655, and 5,456,923, and EP publication 0901786A2.
One problem with trying to use the pure amorphous form of a drug in a drug delivery dosage form is that the solid drug may not be stable physically in the amorphous form. Often the crystalline form of the drug has a lower free energy such that, over time, the amorphous drug will tend to crystallize. This has been observed with the amorphous form of paroxetine mesylate which converts to crystalline paroxetine mesylate, Form A. The rate of crystallization may be influenced by storage conditions, such as temperature and humidity, as well as the constituents of the composition.
Similarly, even if a dispersion of drug and polymer is formed, the drug in the resulting amorphous dispersion of polymer and drug may in some cases be unstable. For example, the dispersion may be physically unstable over time at moderate temperatures and humidities, causing the amorphous drug to separate from the dispersion and/or crystallize. Alternatively, the drug in the amorphous dispersion may be chemically unstable.
Alternatively, it may be difficult or, in some cases, impossible to form a dispersion of the drug and preferred polymer. In particular, the drug and preferred polymer may not both be amenable to a processing method that results in a dispersion of the drug and preferred polymer. For example, when solvent processing is the preferred method for forming the dispersion, the drug and preferred polymer may not both be soluble to a sufficient extent in an appropriate processing solvent to allow formation of the dispersion. In cases where melt processing is preferred, the drug or polymer or both may suffer unacceptable decomposition upon heating to allow the formation of the preferred composition to be practical.
Accordingly, for paroxetine mesylate what would be desirous is a composition comprising that amorphous drug that is physically and/or chemically stable under typical storage conditions, that may be formed via practical processing conditions, and/or that may enhance the bioavailability of paroxetine mesylate. These needs and others that will become apparent to one of ordinary skill are met by the invention, which is summarized and described in detail below.